This research plan is aimed at investigating one of the host cellular defense mechanisms,namely natural or spontaneous cytotoxicity (NK) against tumor cells, which is impared in some patients with cancer. The specific aims of the proposal are as follows: First, the NK activity of host inflammatory cells within the tumor and peripheral mononuclear cells (PMNCs) will be measured. Patients with lung, colon, and breast cancer will be studied. The mechanisms of impared NK activity observed in these patients will be analyzed in terms of depletion of effector cells, inhibition by soluble factors, suppressor cells, accessory cell dysfunction, or redistribution of effector cells. these studies will involve 5 1Cr release assays, surface marker assays of mononuclear inflammatory cells using flow fluorometry, prostaglandin (PG) assays, and other techniques. Second, the role of in vivo production of PGs as one of the mechanisms of cancer-associated depression of NK activity will be studied. Assays for urinary PG metabolites, longitudinal studies of NK activity and in vivo production of PGs before and after tumor resection (and in some instances before and after administration in vivo of PG-synthetase inhibitors) are involved in this study. Third, the role of genetic and environmental factors in the cancer-associated suppression of NK activity will be studied in other individuals at risk for lung cancer such as smokers and uranium miners. Genetic factors will be examined by measurement of NK activity in family members of cancer patients who have impairment of NK fraction. Fourt, in order to develop a unique method to identify the presence of NK effector cells, a monoclonal anti-NK antibody will be developed. This project includes the production of hybridomas. Fifth, we have observed recently that the fucose-binding Lotus tetragonolobus lectin may be a specific probe for the identification of NK cell in selected subjects with the appropriate blood group type. The specificity of this probe will be further established. Overall the proposal is aimed at examining the mechanism of impaired NK function in cancer patients and defining the nature of the NK effector cell.